Many pancreatic cancers secrete glycoproteins and glycolipids that bear a glycan called sialyl-Lewis A (sLeA). The sLeA glycan forms the basis for the Food and Drug Administration-approved cancer antigen 19-9 (CA19-9) blood test, named after the monoclonal antibody first developed against the sLeA glycan. The test is used as an approximate indicator of extent of disease recurrence, but a problem with the CA19-9 antigen is that it is not increased in a substantial proportion of patients. By using a typical cut-off value of 37 U/mL, approximately 25%-35% of patients do not show increases, rendering the test inconclusive for the diagnosis or monitoring of cancer in many patients. However, the test is very specific for cancer at high cut-off values. Therefore, CA19-9 represents an important marker for pancreatic cancer and a good basis on which to build molecular indicators for cancer, but it needs to be improved. After many years of research since the discovery of CA19-9, a biomarker validated to perform better than CA19-9 for pancreatic cancer detection is not yet available. Improving the CA19-9 blood test or identifying another marker to detect cancer among patients with low CA19-9 levels potentially could lead to an improved diagnostic test.
The sLeA glycan is part of a family of glycans called the “Lewis antigens”, named after the discoverer of a series of antigens found on red blood cells comprising a system of blood types. The Lewis glycans generally appear on the termini of oligosaccharides attached to both proteins and lipids. The common feature among the family members is a core N-acetyl-lactosamine (LacNAc), which is a disaccharide of galactose linked to N-acetylglucosamine. The monosaccharides fucose and sialic acid can be attached to the LacNAc in various linkages. A sulfate group also can be attached to the galactose or N-Acetylglucosamine. In the normal pancreas, sLeA appears on the epithelial surfaces of the ducts, and in the cancerous pancreas it can be heavily secreted into the lumen of the proliferating ducts. The increase of sLeA in the blood likely results from accumulation in the stroma followed by leakage into the capillaries or lymph. One reason for the lack of increase in CA19-9 levels is genetics. A glycosyltransferase enzyme that is critical for the biosynthesis of sLeA, fucosyltransferase 3, is inactive in approximately 5% of the North American population as a result of homozygous mutations in the active part of the gene. But the cause of low CA19-9 levels is not clear for patients with wild-type fucosyltransferase 3.
Other members of the Lewis antigens besides sLeA also appear both in the normal and cancerous pancreas. An isomer of sLeA called sialyl Lewis X (sLeX) is up-regulated in the tissue of some pancreatic cancers, and the inventors and others found it increased in the circulation of many pancreatic cancer patients. Some patients have an increase in a glycan detected by the DUPAN-2 monoclonal antibody, identified primarily as type 1 sialyl-LacNAc. And the inventors' previous research also found indirect evidence for additional glycans by comparing patient increases between anti-sLeA antibodies with either broad or narrow specificity.
These observations suggest that diversity exists between pancreatic cancers in the type of glycans they make and secrete into the blood; and that a variety of glycans is secreted, with differences between individual cancers. Thus, to encompass the full range of pancreatic cancers, assays are needed to detect the various antigens that pancreatic cancers are expressing in addition to sLeA, and that are not normally increased under healthy or benign conditions. Improved assays to detect sLeA, or assays to detect the additional cancer-associated glycans could be used to identify a higher percentage of pancreatic cancer patients.